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WO1999041235A1 - Inhibiteurs de la farnesyle transferase - Google Patents

Inhibiteurs de la farnesyle transferase Download PDF

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Publication number
WO1999041235A1
WO1999041235A1 PCT/GB1999/000369 GB9900369W WO9941235A1 WO 1999041235 A1 WO1999041235 A1 WO 1999041235A1 GB 9900369 W GB9900369 W GB 9900369W WO 9941235 A1 WO9941235 A1 WO 9941235A1
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WIPO (PCT)
Prior art keywords
alkyl
benzamido
formula
fluorophenethyl
ylmethylamino
Prior art date
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PCT/GB1999/000369
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English (en)
Inventor
David John Drake
James Michael Wardleworth
Original Assignee
Astrazeneca Uk Limited
Zeneca Pharma S.A.
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Filing date
Publication date
Application filed by Astrazeneca Uk Limited, Zeneca Pharma S.A. filed Critical Astrazeneca Uk Limited
Priority to EP99903834A priority Critical patent/EP1054865A1/fr
Priority to AU24351/99A priority patent/AU2435199A/en
Priority to JP2000531430A priority patent/JP2002503650A/ja
Publication of WO1999041235A1 publication Critical patent/WO1999041235A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/12—Oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • This invention relates to compounds that inhibit famesylation of mutant ras gene products through inhibition of the enzyme farnesyl-protein transferase (FPTase).
  • the invention also relates to methods of manufacturing the compounds, pharmaceutical compositions and methods of treating diseases, especially cancer, which are mediated through famesylation of ras.
  • Ras genes are frequently mutated in tumours.
  • Ras genes encode guanosine triphosphate (GTP) binding proteins which are believed to be involved in signal transduction, proliferation and malignant transformation.
  • GTP guanosine triphosphate
  • H-, K- and N-ras genes have been identified as mutant forms of ras (Barbacid M, Ann. Rev. Biochem. 1987, 56: 779-827).
  • Post translational modification of ras protein is required for biological activity.
  • Famesylation of ras catalysed by FPTase is believed to be an essential step in ras processing.
  • ras is able to attach to the cell membrane for relay of growth signals to the cell interior. In normal cells activated ras is believed to act in conjunction with growth factors to stimulate cell growth.
  • tumour cells it is believed that mutations in ras cause it to stimulate cell division even in the absence of growth factors (Travis J, Science 1993, 260: 1877-1878), possibly through being permanently in GTP activated form rather than cycled back to GDP inactivated form. Inhibition of famesylation of mutant ras gene products will stop or reduce activation.
  • One class of known inhibitors of farnesyl transferase is based on farnesyl pyrophosphate analogues; see for example European patent application EP 534546 from Merck. Inhibitors of farnesyl transferase based on mimicry of the CAAX box have been reported.
  • 2,4-thioproline compounds which contain phenyl, naphthyl or heteroaryl ring which can be substituted by a group of the formula -CONR13-CHR14-COOR17.
  • a range of compounds containing non-acid groups which have farnesyl transferase inhibitory activity. According to one aspect of the present invention there is provided a compound of formula (1):
  • A is of the formula:
  • R 3 is hydrogen, C 2 - 5 alkanoyl, C ⁇ . 4 alkoxycarbonyl, C 2 - 4 alkenyloxycarbonyl, phenylC ⁇ _ 3 alkyl, phenoxycarbonyl, phenylC ⁇ alkoxycarbonyl or C ⁇ . 4 alkyl optionally substituted by carbamoyl, C ⁇ . 4 alkylcarbamoyl, di(C ⁇ . 4 alkyl)carbamoyl, carboxy or C ⁇ _ 4 alkoxy carbonyl;
  • R 4 is hydrogen, C ⁇ _ 4 alkyl, C 2 - 5 alkanoyl, C ⁇ _ 4 alkoxy carbonyl, phenylC ⁇ _ 3 alkyl, benzoyl, heteroarylC,. 3 alkyl or heteroaroyl; D is a linking moiety selected from the following groups written from left to right in formula
  • T is -(CH 2 )m- wherein m is 1-4 and T is optionally monosubstituted with any value of R 5 other than hydrogen ; and ⁇ represents -(CH 2 )mi- wherein ml is 0-4 and Tl is optionally monosubstituted with any value of R5 other than hydrogen);
  • Ar 1 is of the formula (5), (6) or (7):
  • R is hydrogen, Ci ⁇ alkyl, phenylC ⁇ _ 4 alkyl
  • R is hydrogen, Ci ⁇ alkyl, hydroxyC 1 - 4 alkyl, haloC M alkyl, dihaloC M alkyl, C M alkoxy,
  • R 8 is hydrogen, Cj ⁇ alkyl or C 2 - 5 alkanoyl
  • B is phenyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, thienyl, thiazolyl, furyl or oxazolyl, the ring being substituted on ring carbon atoms by Ri and -(CH 2 ) n R 2 ; or B is pyrrolyl, pyrazolyl or imidazolyl, substituted by R 1 and -(CH 2 ) n R 2 (the pyrrolyl, pyrazolyl or -4-
  • A is of the formula (2) or (3)
  • B can also be naphthyl substituted by Ri and -(CH 2 ) n R 2
  • R 1 is of the formula -CONHCH(Ri ⁇ )RH wherein Rio is hydrogen or -(CH 2 ) q -R 12 wherein q is 0-4 and R 12 is hydrogen C ⁇ _ 4 alkylsulfanyl, Cj ⁇ alkylsulfinyl, Cj_ 4 alkylsulfonyl, hydroxy, C ⁇ alkoxy, carbamoyl, N-Ci ⁇ alkylcarbamoyl, N,N-(diC i . 4 alkvl ' )earbamovl.
  • RU is of the formula -CH 2 ORi3 (wherein R 13 is hydrogen, C 1 . alkyl, phenyl, heteroaryl, C 2 - 5 alkanoyl, C ⁇ - alkoxymethyl, phenoxymethyl or heteroaryloxymethyl), of the formula -COR ⁇ 4 or of the formula -CH 2 CORi4 (wherein Ri* is C 1 . 4 alkyl (optionally substituted by halo, cyano, C 2 . 4 alkanoyloxy, hydroxy, Cj_4alkoxy or C ⁇ _4alkanoyl), phenyl, phenylCi-
  • R 11 is morpholinoC ⁇ ⁇ alkyl, pyrrolidin-l-ylC ⁇ . 4 alkyl or piperidin-l-ylC ⁇ - alkyl wherein the morpholine, pyrrolidine and piperidine rings are optionally substituted by C ⁇ . 4 alkyl or C 5 . 7 cycloalkyl; or R 11 is phenyl- 1 -hydroxyC alkyl; or heteroaryl- 1 -hydroxyC M alkyl;
  • R is phenyl or heteroaryl; n is 0, 1 or 2; and phenyl and heteroaryl groups in R 2 , R3, R4, R6, R7 ; Rii (including R 13 and R 14 ), R' 2 , Ar 2 and D are independently optionally substituted on ring carbon atoms by up to three substituents selected from C ⁇ _4alkyl, halogen, hydroxy, C ⁇ _4alkoxy, C j _4alkoxycarbonyl, C ⁇ _4alkanoyl,
  • C ⁇ _4alkanoyloxy amino, C ⁇ alkylamino, di(C ⁇ _4alkyl)amino, Cj ⁇ alkanoylamino, nitro, cyano, carboxy, carbamoyl, N-C ⁇ . 4 alkylcarbamoyl, N,N-(di-C ⁇ - 4 alkyl)carbamoyl, Ci ⁇ alkoxycarbonyl, thiol, C ⁇ alkylsulfanyl, C ⁇ _4alkylsulfinyl,C ⁇ _4alkylsulfonyl,
  • alkyl includes both straight-chain and branched-chain alkyl groups. However references to individual alkyl groups such as "propyl” -5-
  • optically active or racemic forms by virtue of one or more asymmetric carbon atoms
  • the invention includes in its definition any such optically active or racemic form which possesses the property of inhibiting FTPase.
  • the synthesis of optically active forms may be carried out by standard techniques of organic chemistry well known in the art, for example by synthesis from optically active starting materials or by resolution of a racemic form.
  • inhibitory properties against FTPase may be evaluated using the standard laboratory techniques referred to hereinafter.
  • heteroaryl refers to a 5 or 6-membered monocyclic heteroaryl ring containing upto 3 heteroatoms selected from nitrogen, oxygen and sulphur.
  • 'bicyclic heteroaryl' refers to 8 to 10-membered bicyclic aromatic ring systems which contain up to 5 ring heteroatoms selected from nitrogen, oxygen and sulfur and comprises a 6- membered ring fused to a 5 or 6-membered ring.
  • halogen refers to fluorine, chlorine, bromine and iodine.
  • carbamoyl refers to -C(O)NH 2 .
  • BOC refers to tert-butoxycarbonyl.
  • C ⁇ - 4 alkyl examples include methyl, ethyl, propyl, isopropyl, sec-butyl and tert- butyl; examples of C ⁇ alkoxy include methoxy, ethoxy and propoxy; examples of
  • Cj_4alkanoyl include formyl, acetyl and propionyl; examples of C 2 . 5 alkanoyloxy include acetyloxy and propionyloxy; examples of C ⁇ - 4 alkylamino include methylamino, ethylamino, propylamino, isopropylamino, sec-butylamino and tert-butylamino; examples of i-(C 1 - 4 alkyl)amino include di-methylamino, di-ethylamino and N-ethyl-N-methylamino; examples of Cj ⁇ alkanoylamino include acetamido and propionylamino; examples of phenylC ⁇ _ 3 alkyl include benzyl and phenethyl; examples of alkenyloxycarbonyl include allyloxycarbonyl and vinyloxycarbonyl; examples of phenylCi ⁇ alkoxycarbonyl include
  • propylsulfinyl isopropylsulfinyl, sec-butylsulfinyl and tert-butylsulfinyl
  • examples of C ⁇ _4alkylsulfonyl include methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, sec-butylsulfonyl and tert-butylsulfonyl
  • examples of N-(C 1 - alkyl)carbamoyl include N- methylcarbamoyl and N-ethylcarbamoyl
  • alkyl)carbamoyl include N,N-dimethylcarbamoyl and N-methyl-N-ethylcarbamoyl;
  • examples of phenyl- 1 - hydroxyC alkyl include 1 -phenyl- 1-hydroxymethyl and 2-phenyl-l-hydroxyethyl;
  • examples of heteroaryl- 1 -hydroxy C h alky 1 include l-(pyrid-2-yl)-l-hydroxymethyl, 2-(pyrid-2-yl)-l- hydroxyethyl, l-(thiazol-2-yl)-l-hydroxymethyl and 2-(thiazo-2-yl)-l-hydroxyethyl;
  • examples of Cj ⁇ alkanesulfonamido include methanesulfonamido, ethanesulphonamido and propanesulfonamido;
  • 4 alkyl include N,N-dimethylcarbamoylethyl and N-methyl-N-ethylcarbamoylethyl; examples of hydroxyC 1 . 4 alkyl include hydroxymethyl, hydroxyethyl, hydroxypropyl, 2- hydroxypropyl, 2-(hydroxymethyl)propyl and hydroxy butyl; examples of C ⁇ alkoxy methyl include methoxymethyl, ethoxymethyl and propoxymethyl; examples of C ⁇ alkoxyC ⁇ alkyl include methoxyethyl, ethoxyethyl and methoxybutyl; examples of sulfanylC].
  • N-(C ⁇ - 4 alkyl)aminoC 1 - 4 alkyl include N-methyl-aminomethyl and N-ethyl-aminoethyl.
  • Examples of 5- or 6-membered heteroaryl ring systems include imidazole, triazole, pyrazine, pyrimidine, pyridazine, pyridine, isoxazole, oxazole, isothiazole, thiazole and thiophene.
  • Preferred heteroatoms in heteroaryl rings are N and S, especially N. In general, attachment of heterocyclic rings to other groups is via carbon atoms.
  • 5/6 and 6/6 bicyclic ring systems examples include benzofuran, benzimidazole, ben ⁇ liiophene, benzthiazole, benzisothiazole, benzoxazole, benzisoxazole, pyridoimidazole, pyrimidoimidazole, quinoline, isoquinoline, quinoxaline, quinazoline, phthalazine, cinnoline and naphthyridine.
  • Heteroaroyl means heteroarylcarbonyl (heteroaryl-CO-).
  • the ring sp 3 hybridised ring nitrogen in the pyrrolyl, pyrazolyl or imidazolyl rings is the ring nitrogen which can be substituted without becoming quatemised i.e. the ring >NH nitrogen.
  • R 10 in Formula (2) are side chains of lipophilic amino acids including, for example, methionine, phenylglycine, phenylalanine, serine, leucine, isoleucine or valine. L configuration in the corresponding free amino acid is preferred. Examples of amino acid side chains are set out below.
  • A is of the formula (2) or (3).
  • A is of the formula (4).
  • A is of the formula (2) or (3):
  • R 3 is selected from hydrogen, phenylCi. 3 alkoxy carbonyl, C 2 - 4 alkenyloxycarbonyl, C 2 - 5 alkanoyl, carbamoylC ⁇ _ 4 alkyl, N-C 1 . 4 alkylcarbamoylC ⁇ . 4 alkyl or di(C 1 _ alkyl)carbamoylC 1 . alkyl.
  • R 3 is hydrogen.
  • R 4 is hydrogen, C 2 . 5 alkanoyl, C,. 4 alkoxy carbonyl or benzoyl.
  • R 4 is hydrogen, C 2 - 5 alkanoyl or benzoyl.
  • R 4 is hydrogen.
  • B is selected from phenyl, naphthyl, pyridyl or thienyl.
  • B is phenyl or naphthyl.
  • Suitable values for D when it is of the formula -CHN(R5)-T-, include CH2.N(CO.CH2.CHMe2).CH2.CH2; CH2-N(CH2 CH2 CH2OMe).CH2-CH2; CH2.N(CH2. ⁇ Ph.OMe).CH2.CH2; CH2.N(CO.CH2.CHMe2).CH2; CH2N(CO.CH2.CH2.CH2.Me).CH2; CH2N(CO.CH2.CHMe.CH2Me).CH2; CH2N(CO.CH2-CH2.OMe)CH2; CH2N(CO.CH2.pyridin-3-yl).CH2; CH2N(4- methoxybenzyl)CH2; CH2N(CO.CH2.CHMe2)CH2.CH2.CH(Ph); CH2N(CO.CH3)CH2.CH2.CH(Ph); CH2N(CO.CH2.CHMe2)CH2; CH2N(CO.CH3)CH2.CH2.CH(Ph); CH2N(
  • CH 2 N(R 5 )T examples include CH 2 N(CO.CH 2 .CHMe 2 )CH 2 .CH(Ph); CH 2 N (CO.CH 2 pyridin-3-yl)CH 2 CH(Ph); CH 2 N(CO.1 - hydroxy-6-hydroxypyridin -3-yl)CH 2 .CH(Ph); CH 2 N(CO thiazol-2-yl)CH 2 .CH 2 ; and CH 2 N (CO.1 -oxido-6-hydroxypyridin-3-yl) CH 2 .CH 2 .
  • Suitable values for D when it is of the formula -CH2N(R ) - include CH2NH; CH2NMe; CH2N(CO.CH2.CHMe2) and CH2N(CO.CH2.CH2.OMe).
  • a preferred value for - CH 2 NR 5 - is -CH 2 NH 2 -.
  • D is of the formula: -9-
  • piperazine ring is optionally substituted by C M alkoxyC M alkyl, phenoxyC ⁇ alkyl or heteroaryloxyC alkyl.
  • A is of the formula (2) or (3):
  • substituents on the 2 and 3 (or 4 if A is of the formula (3)) positions of the pyrrolidine ring, in compounds of the Formula I are in the cis configuration.
  • Another suitable configuration is the trans configuration.
  • R 7 is hydrogen, C M alkyl, hydroxyC M alkyl, C M alkoxyC M alkyl, C ⁇ alkenyloxyC. ⁇ alkyl, C 2 ⁇ ,alkynyloxyC M alkyl, sulfanylC M alkyl, aminoC M alkyl, N-(Cj. 4 alkyl)aminoC M alkyl or phenylC M alkyl.
  • R is hydrogen or methyl.
  • R is C ⁇ alkyl, hydroxyC ⁇ alkyl, sulfanylC 1 - 4 alkyl, aminoC]. 4 alkyl, N- -10-
  • R is benzyl (optionally substituted by cyano or nitro), methyl, ethyl or hydrogen. More preferably, R6 is 4-cyanobenzyl, 4-nitrobenzyl, methyl or hydrogen.
  • R 7 is preferably hydrogen or methyl.
  • Ari is imidazol-5-yl
  • R 7 is preferably hydrogen and R5 is preferably methyl or cyanobenzyl.
  • p is 1.
  • a preferred heteroaryl value for Ar2 is pyridyl or thiazolyl, especially thiazol-2-yl.
  • Ar 2 is phenyl
  • more preferred optional substituents are fluoro, chloro and cyano.
  • Ar2 is phenyl, it is preferably unsubstituted or monosubstituted. In one aspect, when Ar 2 is phenyl, it is unsubstituted.
  • Ar2 when Ar2 is phenyl, it is monosubstituted in the para position.
  • R8 is hydrogen, methyl or acetyl. Most preferably R8 is hydrogen.
  • B is phenyl, pyridyl, thienyl, thiazolyl, oxazolyl or pyrazolyl.
  • B is phenyl or pyridyl.
  • A is of the formula (2), (3) or (4):
  • B is phenyl or pyridyl.
  • Most preferably B is phenyl.
  • n is 0, B is substituted by Ri in the 4-position and -(CH 2 ) n R 2 in the 3- or 5-position and when n is 1 or 2, then B is preferably substituted by R 1 in the 3- or 5-position and -(CH 2 ) n R 2 in the 4-position.
  • R12 in Rio is hydrogen, methyl, C ⁇ _ 4 alkylsulfanyl, C ⁇ _ 4 alkylsulfonyl, Ci- 4 alkoxy, hydroxy, phenyl or thienyl. More preferably R12 in Rio is methyl, methylsulfanyl or methylsulfonyl, methoxy, hydroxy or carbamoyl. -11-
  • R12 in Rio is methyl, methylsulfanyl or methylsulfonyl.
  • R 12 is methylsulfanyl or methylsulfonyl.
  • Preferred values for Rio include 2-(methylsulfanyl)ethyl, 2-(methylsulfonyl)ethyl, 2-(methoxy)ethyl and methyl.
  • R 13 in R 11 is hydrogen or phenyl.
  • R13 in RU is hydrogen.
  • R14 in RU is C ⁇ . 4 alkyl, phenyl, phenylC 1 . 3 alkyl, heteroaryl, heteroarylC ⁇ alkyl or C 5 - 7 cycloalkylC ⁇ - 3 alkyl.
  • RI 4 in RH is Cj. 4 alkyl, phenyl, phenylC ⁇ _ 3 alkyl or heteroaryl.
  • R 1 in Ri 1 is C ⁇ . 4 alkyl, phenyl or benzyl.
  • R 14 is C alkyl it is optionally substituted by halo, cyano or C 2 . 6 alkanoyloxy.
  • morpholinoC 1 . 4 alkyl is morpholinomethyl
  • pyrrolidin- 1 -ylC 1 . 4 alkyl is pyrrolidin-1-ylmethyl
  • piperidin-l-ylC 1 . 4 alkyl is piperidin-1-ylmethyl.
  • Ri is morpholinomethyl.
  • RU is hydroxymethyl, benzylcarbonyl, 3-(pyridyl)propionyl or morpholinomethyl.
  • R 2 is optionally substituted phenyl, thienyl or thiazolyl.
  • R2 is phenyl more preferred optional substituents are fluoro, chloro and cyano.
  • R2 is phenyl, it is preferably unsubstituted or monosubstituted.
  • R2 when R2 is phenyl, it is unsubstituted.
  • R 2 when R 2 is phenyl, it is monosubstituted in the para position.
  • R is phenyl or 4-fluorophenyl.
  • Preferred values for -(CH 2 )nR 2 include 4-fluorophenyl, phenyl, thiazol-2-yl, 2-(4- fluorophenyl)ethyl and 2-(thiazol-2-yl)ethyl.
  • Particular compounds of the present invention include: (2S)-2- ⁇ 2-(4-fluorophenyl)-4-[ 1 -(4-fluorophenyl)-2-(imidazol- 1 -yl)ethylamino]- benzoylamino ⁇ -4-methylsulfanylbutan-l-ol;
  • the present invention relates to an inhibitor of ras fanesylation of formula (1) : -15-
  • A is of the formula:
  • R 3 is hydrogen, C 2 - 5 alkanoyl, Ci ⁇ alkoxy carbonyl, C 2 - 4 alkenyloxycarbonyl, phenylC ⁇ - 3 alkyl, phenoxycarbonyl, phenylC ⁇ - 3 alkoxycarbonyl or C ⁇ alkyl optionally substituted by carbamoyl, C 1 . 4 alkylcarbam.oyl, di(C ⁇ . 4 alkyl)carbamoyl, carboxy or C ⁇ alkoxy carbonyl; R 4 is hydrogen, C ⁇ . 4 alkyl, C 2 - 5 alkanoyl, C ⁇ - 4 alkoxycarbonyl or phenylC ⁇ 3 alkyl; D is a linking moiety selected from the following groups written from left to right in formula (2) and (3):
  • T is -(CH 2 )m- wherein m is 1-4 and T is optionally monosubstituted with any value of R5 other than hydrogen ; and TJ represents -(CH 2 )mi- wherein ml is 0-4 and Tl is optionally monosubstituted with any value of R 5 other than hydrogen);
  • Ari is of the formula (5), (6) or (7):
  • R is hydrogen, Ci ⁇ alkyl, phenylC ⁇ . 4 alkyl
  • R is hydrogen, C h alky 1, hydroxyC ⁇ alkyl, C ⁇ . 4 alkoxyC ⁇ . 4 alkyl, C 2 . 4 alkenyloxyC ⁇ _ 4 alkyl,
  • R 8 is hydrogen, C ⁇ _ 4 alkyl or C 2 - 5 alkanoyl
  • B is phenyl, pyridyl, pyridazinyl, pyrimidyl or pyrazinyl the ring being substituted on ring carbon atoms by R i and -(CH 2 ) n R ;
  • R 1 is of the formula -CONHCH(Ri ⁇ )Ri l wherein Rio is hydrogen -(CH 2 ) q -Ri2 wherein q is
  • R1 is C ⁇ . 4 alkylsulfanyl, C]- 4 alkylsulfinyl, C ⁇ - 4 alkylsulfonyl, hydroxy, C 1 . 4 alkoxy, carbamoyl, N-C 1 - 4 alkylcarbamoyl, N.NJdiC i --.alkvDcarbamovh Ci ⁇ alkyl, phenyl, thienyl, phenylC ⁇ alkoxy or C alkanoylamino;
  • RU is of the formula -CH 2 OR1 (wherein RI is hydrogen, C h alky 1, phenyl, heteroaryl, C 2 . salkanoyl, C ⁇ alkoxymethoxy, phenoxymethoxy, heteroaryloxymethoxy or C 2 - 5 alkanoyloxy), of the formula -CORI 4 or of the formula -CH 2 CORi4 (wherein RI 4 is C -alkyl, phenylCj.
  • (heteroaryl)ethenyl, 2,2-dihydroxy ethyl or N-methoxy-N-methylamino) or RU is morpholinoC ⁇ _ 4 alkyl, pyrrolidin-l-ylC ⁇ . 4 alkyl or piperidin-l-ylC ⁇ - 4 alkyl wherein the morpholine, pyrrolidine and piperidine rings are optionally substituted by Cj ⁇ alkyl or
  • R 2 is phenyl or heteroaryl; n is 0, 1 or 2; phenyl and heteroaryl groups in R 2 , R 3 , R4, R6, R7 ? Ri 1 5 R12 ? Ar 2 and D are independently optionally substituted on ring carbon atoms by up to three substituents selected from C i _4alkyl, halogen, hydroxy, C 1 _4alkoxy, C ⁇ _4alkoxycarbonyl, C ⁇ _4alkanoyl,
  • C ⁇ _4alkanoyloxy amino, C ⁇ _4alkylamino, di(C ⁇ _4alkyl)amino, C ⁇ 4alkanoylamino, nitro, cyano, carboxy, carbamoyl, N-C ⁇ . 4 alkylcarbamoyl, N,N-(di-C ⁇ . 4 alkyl)carbamoyl, C]. 4 alkoxycarbonyl, thiol, C ⁇ alkylsulfanyl, C ⁇ _4alkylsulfinyl,C ⁇ _4alkylsulfonyl,
  • Compounds of Formula (1) may form salts which are within the ambit of the invention.
  • Pharmaceutically acceptable salts are preferred although other salts may be useful in, for example, isolating or purifying compounds.
  • a suitable pharmaceutically-acceptable salt of the invention when the compound contains an acidic moiety is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base which affords a pharmaceutically-acceptable cation, for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.
  • Solvates for example hydrates, are also within the ambit of the invention and may be prepared by generally known methods.
  • a prodrug is a compound which is converted in the human or animal body to a compound of the formula (1).
  • Various forms of prodrugs are well known in the art. For examples of such prodrug derivatives, see: -18-
  • pro-drugs include in vivo hydrolysable esters of a compound of the Formula I which contains either a carboxy or hydroxy group.
  • Suitable pharmaceutically- acceptable esters for carboxy include Cj.salkyl esters, Cs-scycloalkyl esters, cyclic amine esters, C ⁇ .
  • alkoxymethyl esters for example methoxymethyl, C ⁇ - 6 alkanoyloxymethyl esters for example pivaloyloxymethyl, phthalidyl esters, C 3 - 8 cycloalkoxycarbonyloxyC ⁇ - alkyl esters for example 1-cyclohexylcarbonyloxyethyl; l,3-dioxolen-2-onylmethyl esters for example 5- methyl- 1 ,3 -dioxolen-2-onylmethyl; and C ⁇ - 6 alkoxycarbonyloxyethyl esters for example 1 - methoxycarbonyloxyethyl wherein alkyl, cycloalkyl and cyclicamino groups are optionally substituted by, for example, phenyl, heterocyclcyl, alkyl, amino, alkylamino, dialkylamino, hydroxy, alkoxy, aryloxy or benzyloxy, and may be formed at any carboxy group in
  • a pharmaceutical composition comprising a compound as defined in Formula (1) or an individual compound listed above together with a pharmaceutically-acceptable diluent or carrier.
  • a preferred pharmaceutical composition is in the form of a tablet.
  • compositions of the invention may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation -19-
  • parenteral administration for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular or intramuscular dosing or as a suppository for rectal dosing.
  • compositions of the invention may be obtained by conventional procedures using conventional pharmaceutical excipients, well k . nown in the art.
  • compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and/or preservative agents.
  • Suitable pharmaceutically-acceptable excipients for a tablet formulation include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate, granulating and disintegrating agents such as com starch or algenic acid; binding agents such as starch; lubricating agents such as magnesium stearate, stearic acid or talc; preservative agents such as ethyl or propyl p-hydroxybenzoate, and anti-oxidants, such as ascorbic acid.
  • Tablet formulations may be uncoated or coated either to modify their disintegration and the subsequent absorption of the active ingredient within the gastrointestinal tract, or to improve their stability and/or appearance, in either case, using conventional coating agents and procedures well known in the art.
  • Compositions for oral use may be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin, or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • water or an oil such as peanut oil, liquid paraffin, or olive oil.
  • Aqueous suspensions generally contain the active ingredient in finely powdered form together with one or more suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents such as lecithin or condensation products of an alkylene oxide with fatty acids (for example polyoxethylene stearate), or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol
  • condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides for example polyethylene sorbitan monooleate.
  • the aqueous suspensions may also contain one or more preservatives (such as ethyl or propyl p_-hydroxybenzoate, antioxidants (such as ascorbic acid), colouring agents, flavouring agents, and/or sweetening agents (such as sucrose, saccharine or aspartame).
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil (such as arachis oil, olive oil, sesame oil or coconut oil) or in a mineral oil (such as liquid paraffin).
  • the oily suspensions may also contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set out above, and flavouring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water generally contain the active ingredient together with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients such as sweetening, flavouring and colouring agents, may also be present.
  • the pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions.
  • the oily phase may be a vegetable oil, such as olive oil or arachis oil, or a mineral oil, such as for example liquid paraffin or a mixture of any of these.
  • Suitable emulsifying agents may be, for example, naturally-occurring gums such as gum acacia or gum tragacanth, naturally-occurring phosphatides such as soya bean, lecithin, an esters or partial esters derived from fatty acids and hexitol anhydrides (for example sorbitan monooleate) and condensation products of the said partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening, flavouring and preservative agents.
  • Syrups and elixirs may be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol, aspartame or sucrose, and may also contain a demulcent, preservative, flavouring and/or colouring agent.
  • sweetening agents such as glycerol, propylene glycol, sorbitol, aspartame or sucrose
  • demulcent, preservative, flavouring and/or colouring agent may also be in the form of a sterile injectable aqueous or oily suspension, which may be formulated according to known procedures using -21-
  • a sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example a solution in 1,3-butanediol.
  • Suppository formulations may be prepared by mixing the active ingredient with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Suitable excipients include, for example, cocoa butter and polyethylene glycols.
  • Topical formulations such as creams, ointments, gels and aqueous or oily solutions or suspensions, may generally be obtained by formulating an active ingredient with a conventional, topically acceptable, vehicle or diluent using conventional procedure well known in the art.
  • compositions for administration by insufflation may be in the form of a finely divided powder containing particles of average diameter of, for example, 30 ⁇ or much less, the powder itself comprising either active ingredient alone or diluted with one or more physiologically acceptable carriers such as lactose.
  • the powder for insufflation is then conveniently retained in a capsule containing, for example, 1 to 50mg of active ingredient for use with a turbo-inhaler device, such as is used for insufflation of the known agent sodium cromoglycate.
  • Compositions for administration by inhalation may be in the form of a conventional pressurised aerosol arranged to dispense the active ingredient either as an aerosol containing finely divided solid or liquid droplets.
  • Conventional aerosol propellants such as volatile fluorinated hydrocarbons or hydrocarbons may be used and the aerosol device is conveniently arranged to dispense a metered quantity of active ingredient.
  • the reader is referred to Chapter 25.2 in
  • a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 2 g of active -22-
  • Dosage unit forms will generally contain about 1 mg to about 500 mg of an active ingredient.
  • the size of the dose for therapeutic or prophylactic purposes of a compound of the Formula (1) will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well known principles of medicine.
  • compounds of the Formula (1) are useful in treating diseases or medical conditions which are due alone or in part to the effects of famesylation of ras.
  • a daily dose in the range for example, 0.5 mg to 75 mg per kg body weight is received, given if required in divided doses.
  • a parenteral route is employed.
  • a dose in the range for example, 0.5 mg to 30 mg per kg body weight will generally be used.
  • a dose in the range for example, 0.5 mg to 25 mg per kg body weight will be used.
  • Oral administration is however preferred.
  • Compounds of this invention may be useful in combination with known anti-cancer and cytotoxic agents. If formulated as a fixed dose such combination products employ the compounds of this invention within the dosage range described herein and the other pharmaceutically active agent within its approved dosage range. Sequential use is contemplated when a combination formulation is inappropriate.
  • a compound of Formula (1) or a pharmaceutically-acceptable salt thereof for use as a medicament.
  • a compound of Formula (1) or a pharmaceutically-acceptable salt thereof for use in preparation of a medicament for treatment of a disease mediated through famesylation of ras . -23-
  • a method of treating ras mediated diseases, especially cancer by administering an effective amount of a compound of Formula (1) or a pharmaceutically-acceptable salt thereof, to a mammal in need of such treatment.
  • Diseases or medical conditions may be mediated alone or in part by farnesylated ras.
  • a particular disease of interest is cancer.
  • Specific cancers of interest include:
  • - carcinoma including that of the bladder, breast, colon, kidney, liver, lung, ovary, pancreas, stomach, cervix, thyroid and skin;
  • lymphoid lineage including acute lymphocytic leukemia, B-cell lymphoma and Burketts lymphoma;
  • hematopoietic tumors of myeloid lineage including acute and chronic myelogenous leukemias and promyelocytic leukemia;
  • tumors of mesenchymal origin including fibrosarcoma and rhabdomyosarcoma; and - other tumors, including melanoma, seminoma, tetratocarcinoma, neuroblastoma and glioma.
  • the compounds of Formula (1) are especially useful in treatment of tumors having a high incidence of ras mutation, such as colon, lung, and pancreatic tumors.
  • a composition having one (or a combination) of the compounds of this invention By the administration of a composition having one (or a combination) of the compounds of this invention, development of tumors in a mammalian host is reduced.
  • Compounds of Formula (1) may also be useful in the treatment of diseases other than cancer that may be associated with signal transduction pathways operating through Ras, e.g., neuro-fibromatosis.
  • Compounds of Formula (1) may also be useful in the treatment of diseases associated with CAAX-containing proteins other than Ras (e.g., nuclear lamins and transducin) that are also post-translationally modified by the enzyme farnesyl protein transferase.
  • Ras e.g., nuclear lamins and transducin
  • the compounds of the Formula (1) are primarily of value as therapeutic agents for use in warm-blooded animals (including man), they are also useful whenever it is required to inhibit the effects of activation of ras by famesylation. Thus, they are useful as pharmacological standards for use in the development of new biological tests and in the search for new pharmacological agents. -24-
  • the present invention provides a process for preparing a compound of the formula (I) or a pharmaceutically-acceptable salt, prodrug or solvate thereof which comprises: deprotecting a compound of the formula (8):
  • A' is A or protected A
  • Ri 9 is Ri or protected Ri
  • R20 is R2 or protected R2 and B is as hereinabove defined; wherein at least one protecting group is present; and thereafter if necessary:
  • Protecting groups may in general be chosen from any of the groups described in the literature or known to the skilled chemist as appropriate for the protection of the group in question, and may be introduced by conventional methods.
  • Protecting groups may be removed by any convenient method as described in the literature or known to the skilled chemist as appropriate for the removal of the protecting group in question, such methods being chosen so as to effect removal of the protecting group with minimum disturbance of groups elsewhere in the molecule.
  • a carboxy protecting group may be the residue of an ester-forming aliphatic or araliphatic alcohol or of an ester-forming silanol (the said alcohol or silanol preferably containing 1-20 carbon atoms).
  • carboxy protecting groups include straight or branched chain Ci. ⁇ alkyl groups (for example isopropyl, tJ5utyl);Jower alkoxy lower alkyl groups (for example methoxymethyl, ethoxymethyl, isobutoxymethyl); lower aliphatic acyloxy lower alkyl groups, (for example acetoxymethyl, propionyloxymethyl, butyryloxymethyl, pivaloyloxymethyl); lower alkoxycarbonyloxy lower alkyl groups (for example 1-methoxycarbonyloxyethyl, 1-ethoxycarbonyloxyethyl); phenyl lower alkyl groups (for example benzyl.
  • Ci. ⁇ alkyl groups for example isopropyl, tJ5utyl
  • Jower alkoxy lower alkyl groups for example methoxymethyl, ethoxymethyl, isobutoxymethyl
  • lower aliphatic acyloxy lower alkyl groups for example acetoxymethyl, propiony
  • Methods particularly appropriate for the removal of carboxy protecting groups include for example acid-, base-, metal- or enzymically-catalysed hydrolysis.
  • hydroxy protecting groups include lower alkyl groups (for example t-butyl), lower alkenyl groups (for example allyl); lower alkanoyl groups (for example acetyl); lower alkoxycarbonyl groups (for example tJ3utoxycarbonyl); lower alkenyloxycarbonyl groups (for example allyloxycarbonyl); phenyl lower alkoxycarbonyl groups (for example benzoyloxycarbonyl, r methoxybenzyloxycarbonyl, o ⁇ nitrobenzy loxy carbonyl, p ⁇ nitrobenzy loxy carbonyl) ; tri lower alkylsilyl (for example trimethylsilyl, ⁇ butyldimethylsilyl) and phenyl lower alkyl (for example benzyl) groups.
  • lower alkyl groups for example t-butyl
  • lower alkenyl groups for example allyl
  • lower alkoxycarbonyl groups for example tJ3utoxycarbony
  • amino protecting groups include formyl, aralkyl groups (for example benzyl and substituted benzyl, pimethoxybenzyl, nitrobenzyl and 2,4-dimethoxybenzyl, and triphenylmethyl); di-p ⁇ anisylmethyl and furylmethyl groups; lower alkoxycarbonyl (for example Jmtoxy carbonyl); lower alkenyloxycarbonyl (for example allyloxycarbonyl); phenyl lower alkoxycarbonyl groups (for example benzyloxycarbonyl, r methoxybenzyloxycarbonyl, C iitrobenzyloxycarbonyl, p ⁇ nitrobenzy loxy carbonyl; trialkylsilyl (for example trimethylsilyl and tbutyldimethylsilyl); alkylidene (for example methylidene); benzylidene and substituted bei-izylidene groups.
  • lower alkoxycarbonyl for example Jmtoxy carbonyl
  • Methods appropriate for removal of hydroxy and amino protecting groups include, for example, acid-, base-, metal- or enzymically-catalysed hydrolysis, for groups such as -26-
  • Compounds of the formula (1) and (8) can be formed by: a) reacting a compound of the formula (9) with a compound of the formula (10):
  • a 1 , B, n and R2 are as hereinabove defined and R 2i is Ri° or protected Ri°, R 22 is
  • Ri or protected Ri i and R 3 is hydrogen or C ⁇ . 6 alkyl; and thereafter if necessary: i) removing any protecting groups; ii) forming a pharmaceutically-acceptable salt, prodrug or solvate thereof.
  • Suitable coupling conditions include the following: i) Use of EEDQ at ambient temperature in an organic solvent (e.g. dichloromethane, methanol). -27-
  • oxalyl chloride in an organic solvent (e.g. dichloromethane), DMF in a catalytic amount, in the presence of an organic base (e.g. NMM, triethylamine, DMAP) at 0°C to ambient temperature for 0.5-16 hours.
  • organic solvent e.g. dichloromethane
  • EDC/ HOBT in an organic solvent
  • DCCI/ HOBT in an organic solvent (e.g. DMF, dichloromethane) in the presence of an organic base (e.g. triethylamine).
  • a compound of the formula (9) wherein A is of the formula (2) can be prepared using the methods described in Intemational patent application no. PCT/GB96/01810 or method similar thereto.
  • a compound of the formula (9) wherein A is of the formula (3) can be prepared using the methods described in Intemational patent application no. PCT/GB97/02212 or methods similar thereto.
  • a compound of formula (9) in which D (in the formulae A) is -CO-NR 5 - may be prepared by forming an amide bond between the appropriate thioproline substituted by carboxy in the 2-position and a compound of the formula (12):
  • a compound of formula (9) in which D (in the formula A) is -CO-NR 5 -T- may be prepared by an analogous procedure.
  • Suitable coupling conditions include those described above for the reaction between compounds of the formulae (9) and (10).
  • a compound of formula (9) in which D (in the formulae A) is -CH2NR5-, -CH2O- or -CH2S- may be prepared by reacting the appropriate thioproline substitued in the 2-position by -CH 2 L with a compound of the formula (13):
  • L is a leaving group (e.g. mesyloxy, tosyloxy, halogen) and X is S, O or NR 5 , as appropriate.
  • Suitable coupling conditions include the following: i) Use of an inorganic base (e.g. NaHCO3, NaH, K2CO3, butyllithium) in an organic solvent (e.g. THF, DMF, DMSO) and a temperature of about 65° to 150°C ii) Use of an organic base (e.g. triethylamine, DMAP) in an organic solvent (e.g.
  • THF, dichloromethane, DMA, DMF at a temperature range of room temperature -150°C iii)
  • an inorganic base e.g. KOH, NaOH, K-2CO3
  • organic solvents e.g. dichloromethane
  • phase transfer catalyst e.g. tetrabutylammoniumbromide
  • R24 is triphenylphosphine or -P(O)(O alkyl) 2 -
  • Suitable reaction conditions include the following: i) Use of a base (e.g. potassium carbonate, metal hydride, metal alkoxide) in the presence of an organic solvent (e.g.
  • THF, toluene, DMSO optionally in the presence of an aqueous solvent (2-phase system) and optionally in the presence Of a catalyst complexing agent which solubilises alkali metal ions in non-polar solvents such as 1,4,7,10,13 -pentaoxacyclopentadecane (also called 15-Crown-5) or 1,4,7,10,13, 16-hexaoxacyclooctadecane (also called 18-Crown-6).
  • a catalyst complexing agent which solubilises alkali metal ions in non-polar solvents
  • 1,4,7,10,13 -pentaoxacyclopentadecane also called 15-Crown-5
  • 1,4,7,10,13, 16-hexaoxacyclooctadecane also called 18-Crown-6.
  • a compound of formula (9) in which D (in the formula A) is -CH2-NR 5 - may be prepared by reacting a thioproline substituted in the 2-position by a formyl group with a compound of the formula (12).
  • Suitable coupling conditions include the following: i) Use of a reducing agent (e.g. NaCNBH3, BH3, hydrogen plus catalyst, IJHBE13, di-isobutyl-aluminiumhydride, lithium aluminium hydride, sodium borohydride) in the presence of a suitable solvent e.g. ethanol and acetic acid.
  • the thioproline aldehyde may be prepared by oxidation of the corresponding alcohol under suitable conditions such as use of an oxidising agent (e.g. TPAP, NMM-O) in the presence of an organic solvent (e.g. acetonitrile, dichloromethane) at room temperature.
  • an oxidising agent e.g. TPAP, NMM-O
  • organic solvent e.g. acetonitrile, dichloromethane
  • suitable oxidising agents include chromium oxide, pyridinium chlorochromate, pyridinium dichromate, sodium dichromate, pyridine sulfur trioxide complex and sodium hypochlorite.
  • the thioproline aldehyde may also be prepared by reduction of the corresponding ester under standard conditions using for example diisobutyl-aluminium hydride.
  • the thioproline aldehyde may be prepared by reducing the appropriate N- methoxy-N-methylcarboxamide with
  • -CH2-O-T- or -CH2-S-T- may be prepared by reacting the appropriate thioproline which is substituted in the 2-position with -CH 2 L with a compound of the formula (15): -30-
  • Suitable coupling conditions are as outlined above for the reaction between the thioproline substitued in the 2-position by -CH 2 L and a compound of the formula (13).
  • a compound of formula (9) in which D (in the formula A) is -CH2_NR 5 -SO2- may be prepared by reacting the thioproline which is substituted in the 2-position by -CH 2 NHR5 and a compound of the formula (16):
  • reaction is carried out under standard conditions such as the following: i) Use of an organic base (e.g. di-isopropyl-ethylamine, triethylamine,
  • a compound of formula (9) in which D (in the formula A) is -CH2-NR5-CO-T- may be prepared may be prepared by reacting a thioproline which is substituted in the 2-positon by -CH 2 NHR5 and a compound of the formula (17): -31-
  • the reduction is carried out under standard conditions with standard reagents for example using hydrogenation in the presence of a catalyst such as palladium on charcoal at ambient temperature.
  • a compound of formula (9) in which D (in the formulae A) is -CH 2 NR5-, -CONR5, CH 2 N(R 5 )-T- or -CH 2 N(R5)COT- wherein R5 is not hydrogen, may be prepared from the appropriate compound wherein R5 is hydrogen by introducing the appropriate R 5 by acylation, alkylation etc.
  • a compound of the formula (9) wherein A is of the formula (4) can be prepared using the methods described in European patent application no. 97400207.3 filed on 29 January 1997 and European patent application nos. 97402502.5, 97402503.3, 97402504.1 and 97402505.8 all filed on 22 October 1997.
  • Suitable Wittig reaction conditions include using a polar aprotic organic solvent in the presence of a crown ether and an alkali metal cation, preferably at -50 to -5°C. Cl 8 HPLC -32-
  • Suitable hydrogenation conditions include use of a catalyst, preferably palladium on carbon in the presence of an organic solvent at a non-extreme temperature.
  • a compound of the formula (18) can be prepared by introducing Ari' into a compound of the formula (20):
  • a compound of the formula (20) is conveniently formed from a compound of the formula (21):
  • the compound of the formula (21) may be converted to a compound in which L is bromo by bromination with, for example, N-bromosuccinimide, carbon tetrabromide or bromine, or to a compound in which Ll is chloro by chlorination with, for example, chlorine.
  • the compounds of the formula (18) and (22) are conveniently reacted together under conditions suitable for reductive amination, for example in the presence of a reducing agent and a dehydrating agent.
  • Suitable reducing agents include sodium cyanoborohydride and sodium triacetoxyborohydride.
  • sodium cyanoborohydride titanium tetrachloride is generally added dichloromethane or an alcohol used as solvent.
  • titanium tetrachloride an organic base such as triethylamine is generally added. The reaction usually takes place in the temperature range of -20°C to ambient temperature.
  • titanium tetrachloride is generally used as an activating agent, in an organic solvent such as dichloromethane, in a temperature range of -20°C to ambient temperature.
  • a compound of the formula (22) can be prepared by reducing the related nitro compound with a weak reducing agent such as ferric chloride in the presence of 1,1- dimethylhydrazine or tin chloride or hydrogenation under standard conditions known in the art.
  • the related nitro compound can be formed by introducing -(CH 2 ) n R 20 into a compound of the formula (25): COOP 1
  • n 0 and R20 is phenyl
  • the compound of the formula (25) is conveniently reacted with phenyl boronic acid in the presence of a palladium catalyst such as palladium tetrakis (triphenylphosphine) palladium(O) under conditions known for the Suzuki reaction
  • a palladium catalyst such as palladium tetrakis (triphenylphosphine) palladium(O) under conditions known for the Suzuki reaction
  • An aprotic organic solvent such as dimethyl ether (DME), -34-
  • DMSO dimethylsulphoxide
  • THF THF
  • a base such as sodium bicarbonate, sodium carbonate and sometimes sodium hydroxide.
  • a fluoride such as caesium fluoride could be used instead of the base (J. Org. Chem. 1994, 59, 6095-6097).
  • L2 is bromo.
  • the compound of the formula (25), wherein L 2 is preferably bromo or chloro is conveniently reacted with a benzylzinc bromide or a benzyl magnesium bromide in the presence of a nickel or palladium catalyst, such as bis(triphenylphosphine)palladium (II) chloride or Pd 2 (dibenzylideneacetone) 3 , in an inert organic solvent such as tetrahydrofuran (THF).
  • a nickel or palladium catalyst such as bis(triphenylphosphine)palladium (II) chloride or Pd 2 (dibenzylideneacetone) 3
  • THF tetrahydrofuran
  • n 2 and R20 is phenyl
  • the compound of the formula (25) is conveniently reacted with a styrene under conditions known for the Heck reaction. Briefly this involves an inorganic or organic base such as triethylamine, a palladium catalyst such as bis (o-tolylphosphine)palladium (II) chloride (Ace. Chem. Res. 12, 146-151 (1979) and J. Organometallic Chem. 486 (1995) 259-262).
  • a palladium catalyst such as bis (o-tolylphosphine)palladium (II) chloride
  • the resulting alkene can then be reduced using standard methods known in the art, for example, catalytic hydrogenation.
  • the alkyne could be formed by reacting a compound of the formula (25) wherein L is triflate or bromo with a phenyl acetylene in the presence of an organic base such as triethylamine and a palladium catalyst such as tetrakis (triphenylphosphine)palladium.
  • an organic base such as triethylamine
  • a palladium catalyst such as tetrakis (triphenylphosphine)palladium.
  • a compound of the formula (9) wherein E (in A) is of the formula >CH-N(R8)CH 2 - is conveniently prepared by reacting together compounds of the formulae (18) and (26):
  • the compounds of the formula (18) and (26) are conveniently reacted together under conditions suitable for reductive amination, for example in the presence of a reducing agent and a dehydrating agent.
  • Suitable reducing agents include sodium cyanoborohydride and sodium triacetoxyborohydride.
  • sodium cyanoborohydride is used, titanium tetrachloride or 3A or 4A molecular sieves may be used as the dehydrating agent, in dichloromethane or an alcohol as solvent.
  • an organic base such as triethylamine is generally added. The reaction usually takes place in the temperature range of -20°C to ambient temperature.
  • 4A molecular sieves are generally used as the dehydrating agent, in an organic solvent such as dichloromethane, in a temperature range of -20°C to ambient temperature. (Also see Synthesis 135, 1975; Org. Prep. Proceed. Int. ii, 201, 1979).
  • a compound of the formula (26) can be prepared by reducing the related nitro compound with a weak reducing agent such as ferric chloride in the presence of 1 , 1 - dimethylhydrazine or tin chloride or hydrogenation, under standard conditions known in the art.
  • a weak reducing agent such as ferric chloride
  • the related nitro compound can be formed by introducing -(CH 2 ) n R 3 into a compound of the formula (27):
  • Ari', AR 2 ', B, Pi, n and R 2 are as hereinabove defined.
  • a compound of the formula (28) and a compound of the formula (29) are conveniently reacted together under conditions known for the Mitsunobu reaction.
  • This typically involves reacting the reagents together in the presence of di(C ⁇ . 4 alkyl)azodicarboxylate or V, V- (azodicarbonyl) dipiperidine and a phosphorous reagent such as tributylphosphine, triphenylphosphine or diphenylpyridylphosphine in an inert solvent such as toluene, benzene, tetrahydrofuran (THF) and dichloromethane, dioxan or diethylether, at non-extreme temperatures such as in the range -20°C to ambient temperature, (see Progress in the
  • a compound of the formula (28) can be prepared by reducing a compound of the formula (18) as hereinabove defined.
  • Suitable reducing agents include sodium borohydride and lithium aluminium hydride.
  • an alcohol is used as solvent in a temperature range of ambient temperature to 60°C with the former and ether or THF with the latter.
  • the compound of the formula (29) can be formed by introducing -(CH 2 ) n R 20 into a compound of the formula (30):
  • B, Pi and L2 are as hereinabove defined and P 2 is a hydroxy protecting group.
  • a compound of the formula (9) wherein E (in A) is of the formula >CHOCH 2 - is conveniently prepared by reacting together compounds of the formula (28) and (31):
  • R 2 , n and P are as hereinabove defined and Ll is a leaving group.
  • a compound of the formula (31) is typically formed by introducing a leaving group into a compound of the formula CH 3 -B(-COOPi)-(CH 2 ) n R 20 .
  • L i bromo
  • bromination can be carried out using N-bromosuccinimide, carbon tetrabromide or bromine.
  • L chloro
  • a chlorinating agent such as chlorine could be used and when Ll is mesyloxy or tosyloxy, the methyl group is generally oxidised to the alcohol (or oxidised to the carboxylic acid and then reduced to the alcohol) and the hydroxy group converted to mesyloxy or tosyloxy with, for example, mesyl chloride or tosyl chloride.
  • the compound of the formula CH3-B(-COOP i )-(CH 2 ) n R 20 could be formed by introducing -(CH 2 ) n R 2() into a compound of the formula (32):
  • An aprotic organic solvent such as dimethyl ether (DME), dimethylsulphoxide (DMSO) or THF is generally used and a base such as sodium bicarbonate, sodium carbonate and sometimes sodium hydroxide.
  • DME dimethyl ether
  • DMSO dimethylsulphoxide
  • THF THF
  • a base such as sodium bicarbonate, sodium carbonate and sometimes sodium hydroxide.
  • a fluoride such as caesium fluoride could be used instead of the base (J. Org. Chem. 1994, 59, 6095-6097).
  • L 2 is bromo or triflate.
  • the compound of the formula (12), wherein L 2 is preferably bromo or chloro is conveniently reacted with a phenylzinc chloride or a phenyl- magnesium bromide in the presence of a nickel or palladium catalyst, such as bis(triphenylphosphine)palladium (12) chloride or Pd 2 (dba) 3 , in an inert organic solvent such as tetrahydrofurna (THF).
  • a nickel or palladium catalyst such as bis(triphenylphosphine)palladium (12) chloride or Pd 2 (dba) 3
  • THF tetrahydrofurna
  • a compound of the formula (10) is typically prepared from a compound of the formula
  • a compound of formula NH 2 CH(R 2 i)COOH can be reduced to a compound of the formula
  • R 22 is hydroxymethyl with a reducing agent such as lithium aluminium hydride.
  • the compound of the formula (10) wherein R 22 is hydroxymethyl and the amino group is suitably protected can then be alkylated or acylated as appropriate to form compounds of the formula (10) wherein R 22 is of the formula -CH 2 ORi 3 .
  • a compound of the formula (10) wherein R 22 is of the formula -COR14 can be formed via the intermediate NH 2 CH(R 2 i)CON(OMe)Me which itself is formed by reacting
  • a compound of the formula NH 2 CH(R 2 i)CON(OMe)Me can be converted to the corresponding dimethylphosphono compound (NH 2 CH(R 2 i)COP(O)(OMe) 2 ) by reacting the former compound with dimethylmethylphosphonate in the presence of a strong base such as n-butyl -39-
  • a compound of the formula (10) can be formed by reacting the dimethylphosphono compound with the appropriate aldehyde or ketone under conditions known for the Wittig or Emmons-Horner reactions.
  • a compound of the formula (10) wherein R 22 is morpholinomethyl, pyrrolidin-1- ylmethyl or piperidin-1-ylmethyl is conveniently prepared by reacting NH 2 CH(R 2 i)COOH with the appropriate heterocyclic ring under standard amide bond forming conditions to form a compound of the formula (10), wherein RU is heterocyclylcarbonyl, and subsequently reducing the carbonyl group to a methyl group with a reducing agent such as lithium aluminium hydride.
  • a compound of the formula NH 2 CH(R 2 i)COOH can be extended by one carbon length to produce a compound of the formula NH 2 CH(R 2 i)CH 2 COOH using the Amdt-Eistert homologation method.
  • a compound of the formula NH 2 CH(R 2 i)CH 2 COOH and homologues may be used to prepare a compound of the formula NH 2 CH(R 2 i) R 22 wherein R 22 is of the formula -CH 2 CORi4, morpholino C ⁇ _ 4 alkyl, pyrrolidin-l-ylC]. 4 alkyl or piperidin-l-ylC ⁇ _ 4 alkyl.
  • a compound of the formula (11) can be reduced to a compound of the formula (1) or (4) using standard conditions.
  • R 23 when R 23 is hydrogen, the reduction can be carried out using sodium borohydride and ethylchloroformate (for example see Synthesis 1990, 299) and when R 23 is alkyl, using a reducing agent such as lithium borohydride or sodium borohydride in an organic soluent such as THF.
  • the compound of the formula (11) can be prepared by forming an amide bond between a compound of the formula (9) and a compound of the formula NH 2 CH(R 2 i)COOPi wherein Pi is a carboxy protecting group and subsequently removing the protecting group.
  • a compound of the formula (1) or (4) which contains a methylsulfinyl or methylsulfonyl group may be prepared by oxidising the appropriate methylsulfanyl compound.
  • a methylsulfanyl group is typically oxidised to methylsulfinyl using sodium metaperiodate in an organic solvent such as methanol.
  • a methylsulfanyl group can be oxidised to methylsulfonyl using metachloroperbenzoic acid or oxone. Many other suitable oxidising agents are known in the art. -40-
  • a compound of the formula (4) is prepared by reacting together compounds of the formulae (9) and (10).
  • Optional substituents in a compound of the formula (1) and (4) and intermediates in their preparation may be converted into other desired optional substituents.
  • a nitro group could be reduced to an amino group, a hydroxy group alkylated to a methoxy group, or a bromo group converted to an alkylthio group.
  • an acyl group or alkyl group may be introduced into an activated benzene ring using Friedel-Crafts reactions, a formyl group by formylation with titanium tetrachloride and dichloromethyl ethyl ester, a nitro group by nitration with concentrated nitric acid concentrated sulphuric acid and bromination with bromine or tetra(n-butyl)ammonium tribromide.
  • FPT Farnesyl protein transferase
  • the substrate for FPT was Kras (CVIM C-terminal sequence).
  • the cDNA for oncogenic val 12 variant of human c-Ki-ras-2 4B was obtained from the plasmid pSWl 1-1 (ATCC). This was then subcloned into the polylinker of a suitable expression vector e.g. pIC147.
  • the Kras was obtained after expression in the E. coli strain, BL21. The expression and purification of -41-
  • the farnesyl transferase solution for the assay contained the following: dithiothreitol 5 (DTT)(0.6ml of 7.7mg/ml), TRIS buffer (0.6ml), aprotinin (0.48ml), distilled water (1.2ml), farnesyl transferase (0.6ml of the crude enzyme preparation prepared as described above), zinc chloride (12 ⁇ l of 5mM). This was left at ambienttemperature for 30 minutes. After this incubation 60 ⁇ l Ki-ras solution was added and the whole left to incubate for a further 60 minutes prior to use in the assay.
  • DTT dithiothreitol 5
  • TRIS buffer 0.6ml
  • aprotinin 0.48ml
  • distilled water 1.2ml
  • farnesyl transferase 0.6ml of the crude enzyme preparation prepared as described above
  • zinc chloride (12 ⁇ l of 5mM
  • DMEM Dulbecos Modified Essential Medium
  • FCS foetal calf serum
  • HER313A cells were seeded at 200,000 cells/well in a volume of 2.5ml in a 6 well tissue culture plate. After an overnight incubation at 37°C in 10% CO 2 the medium was removed and replaced with methionine-free minimal essential medium (MEM) and the cells
  • MIA PaCa 2 cells (American Tissue Culture Collection Accession Number: CRL-1420) were routinely cultured in Dulbecos Modified Essential Medium (DMEM) plus 10% FCS in a 162 cm 2 tissue culture flask .
  • DMEM Dulbecos Modified Essential Medium
  • FCS 5% charcoal dextran treated stripped FCS
  • Test compound was then added (lO ⁇ l) and the cells incubated for 6 days as described above. On days 1, 2, 3 and 6 the cells were monitored for signs of mo ⁇ hological change and toxicity. On day 6 the cells were removed from the plate using trypsin EDTA and counted to determine the proliferation rate.
  • melting points are uncorrected and were determined using a Mettler SP62 automatic melting point apparatus or an oil-bath apparatus; melting points for the end-products of the Formula (1) were determined after crystallisation from a conventional organic solvent such as ethanol, methanol, acetone, ether or hexane, alone or in admixture; and
  • Lithium borohydride (0.066 g ; 3J mmol) was added at 0°C to a suspension of methyl (2S)-2- ⁇ 2-(4-fluorophenyl)-4-[ 1 -(4-fluorophenyl)-2-(imidazol- 1 -yl)ethylamino jbenzoyl amino ⁇ -4-methylsulfanylbutyrate (0.846 mg ; 1.5 mmol) in a mixture of THF (40 ml) and ether (10 ml). After stirring at ambient temperature overnight, the mixture was acidified at pH with 12N HCl and evaporated to dryness.
  • the starting material was prepared as follows:
  • Oxalyl chloride (9.35 g ; 0.074 mol) was added to a solution of 2-(4-fluorophenyl)-4- nitrobenzoic acid (17.5 g ; 0.067 mol) in methylene chloride (150 ml). After addition of DMF (3 drops), the mixture was stirred at ambient temperature for 2 hours. After evaporation to dryness the residue was redissolved in methylene chloride (100 ml) ; methanol (50 ml) and DMAP (8.2 g ; 0.067 mol) was added at 0°C. After stirring at ambient temperature for 2 hours, the mixture was evaporated to dryness.
  • Titanium chloride (2.86 ml ; 26 mmol) was added portionwise to a solution of methyl 4-amino-2-(4-fluorophenyl)benzoate (5 g ; 20 mmol), l-(4-fluorophenyl)-2-(imidazol-l-yl) ethanone (4.08 g ; 20 mmol) and triethylamine (8.4 ml ; 60 mmol) in dichloromethane (120 ml) at 0°C under argon atmosphere. After stirring overnight at ambient temperature, sodium cyanoborohydride (1.4 g ; 0.22 mmol) in solution in methanol (10 ml) was added at 0°C.
  • the starting material was prepared as follows :
  • Triflic anhydride (170 ml ; 1.01 mol) was added to a solution of methyl 2-hydroxy-4- methylbenzoate (153 g ; 0.92 mol) in pyridine (1.5 1), at 0°C, The mixture was stirred at ambient temperature ovemight. After evaporation of the pyridine, the residue was acidified to pH 3.5 with 6N HCl and extracted with ether. The organic phase was evaporated and the residue purified by flash column chromatography eluting with a gradient of 0-5% ethyl acetate - 51 -
  • Tetrakis(triphenylphosphine) palladium (9 g ; 7.8 mmol) and ethanol (780 ml) was added to a suspension of methyl 4-methyl-2-trifluoromethanesulphonyloxybenzoate (58 g; 0J95 mol), 2M aqueous solution of sodium carbonate (250 ml ; 0.5 mol), 4- fluorophenylboronic acid (30 g ; 0.214 mol) and lithium chloride (16.5 g ; 0.39 mol) in toluene (1.65 ml), under an argon atmosphere, The mixture was refluxed for 4 hours, diluted with ethyl acetate (1 1) and washed with aqueous sodium hydroxide solution IN (1 1).
  • the starting material was prepared as follows: trans-4-Hydroxy-L-proline (50.0 g) was dissolved in 0.5M aqueous sodium hydroxide solution (763 mL) and THF (750 mL) and cooled to 4°C. Boc-O-Boc (91.5 g) was added and the reaction stirred ovemight, warming to RT. The THF was removed in vacuo and the solution diluted with water (1000 mL), acidified to pH2.5 with potassium hydrogen sulphate (51.9 g) and saturated with salt. The yellow emulsion was extracted twice with ethyl acetate (total 2500 mL).
  • Glacial acetic acid (23.6 g, 392.5 mmol), followed by sodium cyanoborohydride (7.45 g, 118 mmol) was added and the mixture stirred at room temperature under an inert atmosphere for 72 h.
  • the mixture was filtered through celite (545) and evaporated.
  • the residues were dissolved in ethyl acetate (600 mL), washed with saturated aqueous sodium bicarbonate solution (3x100 mL) and brine (3x100 mL), dried (MgSO 4 ), filtered and evaporated to give a brown oil (80 g).
  • Methyl 5-amino-2-(4-fluorophenylethyl)benzoate was prepared as follows: A mixture of methyl 2-bromo-5-nitrobenzoate (5 g), 4-fluorostyrene (3.5 g), tributylamine (0.39 g), bis-(triphenylphosphine)-palladium(II)chloride (0.3 g), sodium bicarbonate(2.65 g) and water (30 ml) was stirred and heated at reflux under an argon atmosphere for 1.5 hours.
  • Pentafluorophenyl trifluoroacetate (9 mL, 53 mmol) was added to a stirred solution of 2-(4-fluorophenethyl)-5-((2S,4S)- 1 -tert-butoxycarbonyl-4-tritylsulfanylpyrrolidin-2- - 59 - ylmethylamino)benzoic acid (30 g, 39.25 mmol estd.) in DMF (350 mL) and pyridine (4.3 mL,53 mmol) at room temperature under an inert atmosphere. The resulting solution was allowed to stir for 30 minutes.
  • the starting material was prepared as follows:
  • aqueous phase was extracted with ethyl acetate (3x100 mL) and the combined organics washed with IN citric acid (3x60 mL), saturated aqueous sodium bicarbonate solution (3x60 mL) and brine (2x60 mL), dried (MgSO 4 ), filtered and evaporated to yield
  • the starting material was prepared as follows: n-Butyl lithium in hexane (1.6M) (33 mL, 52.8 mmol) was added to a stirred solution of dimethyl methylphosphonate (7.56 g, 61 mmol) in THF (100 mL) at -70°C under an inert atmosphere and the solution allowed to stir for lh. A solution of (2S)-N-methoxy-N-methyl- 2-tert-butoxycarbonylamino-4-methylsulfanylbutyramide (2.92 g, 10 mmol) in THF (20 mL) was added dropwise and the mixture stirred for an additional lh.
  • Pentafluorophenyl 2-(4-fluorophenethyl)-5-((2S,4S)- 1 -tert-butoxycarbonyl-4- tritylsulfanylpyrrolidin-2-ylmethylamino)benzoate (1J g, 1.25 mmol) was coupled with (3S)- l-methylsulfanyl-4-oxo-6-(pyrid-3-yl)hex-3 -amine (2J4 g, 3.75 mmol estd.) using a similar method to that of Example 9 give (4S)-4-[2-(4-fluorophenethyl)-5-((2S,4S)-lJert- butoxycarbonyl-4-tritylsulfanylpyrrolidin-2-ylmethylamino)benzamido]-6-methylsulfanyl-l- (pyrid-3-yl)hexan-3-one as a colourless oil (1.0 g,
  • the starting material was prepare as follows:
  • the starting material was prepared as follows:
  • (2S)-2-amino-4-methoxybutan-l-ol was coupled with pentafluorophenyl 2-(4- fluorophenethyl)-5-((2S,4S)-l-tert-butoxycarbonyl-4-tritylsulfanylpyrrolidin-2- ylmethylamino)benzoate (2.0 g; 2.26 mmol) using a similar procedure to that used in the equivalent step in Example 10.
  • the starting material was prepared as follows :
  • the starting material was prepared as follows: l-Amino-3-phenyl-2-propanone (RN 135608-75-2 ) (2.05g , 5.45mmol ) was added to a stirred solution of pentafluorophenyl 2-(4-fluorophenethyl)-5-((2S,4S)-l- tertbutoxycarbonyl-4-tritylsulfanylpyrrolidin-2-ylmethylamino)benzoate (1.61g,1.82 mmol ), HOBT (320 mg , 2.37mmol ) and NMM (3.68g , 36.4mmol ) in DMF (25mL). The mixture was stirred under an inert atmosphere at room temperature for 18 hours.
  • reaction mixture was evaporated and the residues dissolved in ethyl acetate (150 mL) washed with sodium hydrogen carbonate (3x50 mL), brine (2x50mL), dried (MgSO 4 ), filtered and evaporated to a crude gum.
  • the starting material was prepared as follows : 1.6M n-Butyl-lithium in hexanes (32mL,50.0mmol) was added to a solution of 4-picoline (4.65g , 50.0 mmol) in THF (200mL) at -70C. After 10 minutes, a solution of (S)-2-(tert- butoxycarbonylamino)-N-methoxy- N-methylpropionamide (RN 87694-49-3), (2.92g, 10.0 mmol) in THF (75 mL ) was added and the mixture stirred for 2 hours at -70°C.
  • the starting material was prepared as follows: A mixture of methyl-2-bromo-5-nitrobenzoate (50.0g , 192.0mmol ), TMS-acetylene
  • Example 7 to give (3S)-3- ⁇ 2-[2-(thiazol-2-yl)ethyl]-5-((2S,4S)-l-tert-butoxycarbonyl-4- tritylsulfanylpyrrolidin-2-ylmethylamino)benzamido ⁇ -l-phenylpentan-2-one, (1.33g, 71%>) as a yellow oil.
  • Example 16a f3S)-3-r2-(4-Fluorophenethvn-5-((2S.4S)-4-sulfanylpyrrolidin-2- ylmethylamino)benzamido]-l-(2-fluorophenyl)-5-methylsulfanylpentan-2-one
  • the starting material was prepared as follows: (2S) - N-Methoxy-N-methyl-2-tert-butoxycarbonylamino-4-methysulfanylbutyramide (8.76g ,30.0 mmol ) was treated with 2-fluorobenzyl magnesium chloride (100 mmol solution in THF) using a similar method to the equivalent step in Example 7 to give (3S)-3-tert- butoxycarbonylamino-l-(2-fluorophenyl)-5-methylsulfanylpentan-2-one as a colourless crystalline solid ,10.0g ( 98%).
  • the starting materials was prepared as follows :
  • the starting material was prepared as follows:
  • the starting material was prepared as follows :
  • the starting material was prepared as follows:
  • the starting material was prepared as follows : (2S)-2-[2-(4-Fluorophenethyl)-5-((2S,4S)-l-tert-butoxycarbonyl-4-tritylsulfanylpyrrolidin-2- ylmethylamino)benzamido]- 1 -(pyridin-2-yl)-4-methylsulfanylbutan- 1 -one (454mg, 0.5mmol) was reduced using a similar method to the equivalent step in Example 16 to give (2S)-2-[2-(4- fluorophenethyl)-5-((2S,4S)-l-tert-butoxycarbonyl-4-tritylsulfanylpyrrolidin-2- ylmethylamino)benzamido]-l-(pyridin-2-yl)-4-methylsulfanylbutan-l-ol (450mg, 99%). MS (ES+) m z 911 (MH+)
  • the starting material was prepared as follows:
  • reaction mixture was quenched with a saturated aqueous solution of ammonium chloride (lOOmL) and extracted with ethyl acetate (4x50mL). The combined organic phases were washed with brine (2x75mL), dried
  • the starting material was prepared as follows:
  • the starting material was prepared as follows:
  • the starting material was prepared as follows:
  • 1.6M n-Butyl lithium in hexanes (6.3mLJ0Jmmol) was added dropwise to a stirred solution of thiazole (800mL,l 1.3mmol) and TMEDA (1.5mL, 9.96mmol) in THF (lOOmL) at -70°C under an inert atmosphere. The internal temperature was allowed to warm to -50°C over 30 minutes and the solution was re-cooled to -70°C.
  • the starting material was prepared as follows : (2S)-2-[2-(4-Fluorophenethyl)-5-((2S,4S)- 1 Jert-butoxycarbonyl-4-tritylsulfanylpyrrolidin-2- ylmethylamino)benzamido]- 1 -(thiazol-2-yl)-4-methylsulfanylbutan- 1 -one (400mg, 44mmol) was reduced with sodium borohydride using a similar method to the equivalent step in Example 16 to give (2S)-2-[2-(4-fluorophenethyl)-5-((2S,4S)-l-tert-butoxycarbonyl-4- tritylsulf- ylpy ⁇ olidin-2-ylmethylamino)benzamido]-l-(thiazol-2-yl)-4-methylsulfanylbutan- l-ol as a colourless gum (360mg, 90%).
  • the starting material was prepared as follows: Pentafluorophenyl 2-(4-fluorophenethyl)-5-((2S,4S)- 1 -tertbutoxycarbonyl-4- tritylsulfanylpyrrolidin-2-ylmethylamino)benzoate (lg,lJ3mmol) was coupled with serinol 99
  • the starting material was prepared as follows:
  • Pentafluorophenyl 2-(4-fluorophenethyl)-5-((2S,4S)- 1 -tertbutoxycarbonyl-4- tritylsulfanylpyrrolidin-2-ylmethylamino)benzoate (lJ7g,1.32mmol) was coupled with (1S)- 3 -acetyloxy- l-methyl-2-oxopropylamine (estd.
  • the starting material was prepared as follows: Sodium borohydride (2.3g,62.5mmol) was added portionwise to a stirred solution of (2S,4S)- 1 -tert-butoxycarbony 1-4-trity lsulfanylpyrrolidin-2-y lcarboxaldehyde ( 19.7g,41. ⁇ mmol) in - 102 - methanol (300mL) at room temperature under an inert atmosphere. The mixture was stirred for 20 minutes and evaporated to dryness. The residues were partitioned between water
  • the starting material was prepared as follows: n-Butyl lithium (39.4 ml, 0.39 mol; 10M solution in hexane) was added dropwise to a stirred solution of 2-bromothiazole (32 ml, 0.36 mol) in dry diethyl ether (350 ml) under nitrogen at -78°C maintaining the temperature below -65°C. The solution was stirred for 1 hour at -70°C and tributyltin chloride (97 ml, 0.36 mol) as a solution in diethyl ether (150 ml) was added. After stirring for 3.5 hours at -78°C, the reaction was allowed to warm to room temperature - 105 - and water (200 ml) added.
  • the starting material was prepared as follows: 108 -

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Abstract

La présente invention concerne un composé de la formule (1) dans laquelle A correspond à la formule (2), (3) ou (4), et dans laquelle B représente phényle, pyridyle, pyridazinyle, pyrimidyle, pyrazinyle, thiényle, thiazolyle, furyle ou oxazolyle, le noyau étant substitué sur les atomes de carbone du cycle par R1 et -(CH¿2)nR?2; ou bien B représente pyrrolyle, pyrazolyle ou imidazolyle, et lorsque A correspond à la formule (2) ou (3), B peut également représenter naphtyle substitué par R1 et -(CH¿2?)nR?2; R1¿ correspond à la formule -CONHCH(R10)R11 dans laquelle R11 correspond à la formule -CH¿2?OR?13, -COR14¿ ou -CH¿2COR?14, ou bien R11 représente morpholino-alkyle C¿1-4?, pyrrolidin-1-yl-alkyle C1-4, ou pipéridin-1-yl-alkyle C1-4; ou bien R?11¿ représente phényl-1-hydroxy-alkyle C¿1-4?, ou hétéroaryl-1-hydroxy-alkyle C1-4; R?2¿ représente phényle ou hétéroaryle, et n vaut 0, 1 ou 2. L'invention concerne également un promédicament, un solvate ou sel de ce composé, acceptable sur le plan pharmacologique. Elle concerne encore des procédés de préparation de ces composés, leur utilisation en tant qu'agents thérapeutiques, ainsi que des compositions pharmaceutiques les contenant. On utilise notamment ces composés dans la thérapie du cancer.
PCT/GB1999/000369 1998-02-10 1999-02-04 Inhibiteurs de la farnesyle transferase WO1999041235A1 (fr)

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WO2001014314A1 (fr) * 1999-08-20 2001-03-01 Nippon Kayaku Kabushiki Kaisha Derives de benzene a substituants aromatiques et procedes de preparation de ceux-ci
WO2001046137A1 (fr) * 1999-12-22 2001-06-28 Astrazeneca Ab Inhibiteurs de farnesyltransferase
WO2001046138A1 (fr) * 1999-12-22 2001-06-28 Astrazeneca Ab Inhibiteurs de farnesyl proteine transferase
US6271418B1 (en) 2000-02-22 2001-08-07 Nippon Kayaku Co., Ltd. Process for preparing (hetero) aromatic substituted benzene derivatives
US6414145B1 (en) * 1997-01-29 2002-07-02 Zeneca Limited Imidazolyl compounds as inhibitors of farnesyl-protein tranferase
WO2001053275A3 (fr) * 2000-01-17 2003-04-17 Bayer Ag Arylcetones substituees
US7432281B2 (en) 2003-10-07 2008-10-07 Renovis, Inc. Amide derivatives as ion-channel ligands and pharmaceutical compositions and methods of using the same
US7576099B2 (en) 2005-02-28 2009-08-18 Renovis, Inc. Amide derivatives as ion-channel ligands and pharmaceutical compositions and methods of using the same

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CN101896457A (zh) * 2007-10-22 2010-11-24 幽兰研究实验室有限公司 组蛋白脱乙酰基酶抑制剂

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WO1997006138A1 (fr) * 1995-08-04 1997-02-20 Zeneca Limited Derives de 4-mercaptopyrrolidine en tant qu'inhibiteurs de farnesyle transferase

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EP0696593A2 (fr) * 1994-08-11 1996-02-14 Bristol-Myers Squibb Company Inhibiteurs de la farnesyl protéine transférase
WO1997006138A1 (fr) * 1995-08-04 1997-02-20 Zeneca Limited Derives de 4-mercaptopyrrolidine en tant qu'inhibiteurs de farnesyle transferase

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THERESA M. WILLIAMS ET AL.: "2-Substitited piperazines as constrained amino acids. Application tot the synthesis of potent, non carboxylic acid inhibitors of farnesyltransferase.", JOURNAL OF MEDICINAL CHEMISTRY., vol. 39, no. 7, - 1996, WASHINGTON US, pages 1345 - 1348, XP002101848 *

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6414145B1 (en) * 1997-01-29 2002-07-02 Zeneca Limited Imidazolyl compounds as inhibitors of farnesyl-protein tranferase
WO2001014314A1 (fr) * 1999-08-20 2001-03-01 Nippon Kayaku Kabushiki Kaisha Derives de benzene a substituants aromatiques et procedes de preparation de ceux-ci
US6777438B2 (en) 1999-12-22 2004-08-17 Astrazeneca Ab Inhibitors of farnesyl protein transferase
WO2001046137A1 (fr) * 1999-12-22 2001-06-28 Astrazeneca Ab Inhibiteurs de farnesyltransferase
WO2001046138A1 (fr) * 1999-12-22 2001-06-28 Astrazeneca Ab Inhibiteurs de farnesyl proteine transferase
US7101897B2 (en) 1999-12-22 2006-09-05 Astrazeneca Ab Farnesyl transferase inhibitors
RU2259997C2 (ru) * 1999-12-22 2005-09-10 Астразенека Аб Ингибиторы фарнезилтрансферазы
WO2001053275A3 (fr) * 2000-01-17 2003-04-17 Bayer Ag Arylcetones substituees
US6864219B2 (en) 2000-01-17 2005-03-08 Bayer Aktiengesellschaft Substituted aryl ketones
US6340772B2 (en) 2000-02-22 2002-01-22 Nippon Kayaku Co., Ltd. Process for preparing (hetero) aromatic substituted benzene derivatives
US6271418B1 (en) 2000-02-22 2001-08-07 Nippon Kayaku Co., Ltd. Process for preparing (hetero) aromatic substituted benzene derivatives
US7432281B2 (en) 2003-10-07 2008-10-07 Renovis, Inc. Amide derivatives as ion-channel ligands and pharmaceutical compositions and methods of using the same
US7576099B2 (en) 2005-02-28 2009-08-18 Renovis, Inc. Amide derivatives as ion-channel ligands and pharmaceutical compositions and methods of using the same

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